West Nile virus (WNV)-induced neurological disease has become an increasing public health concern in North America. Although immune responses to WNV have been the subject of intense investigation, the role of immune-mediated pathology in WNV-induced neurological diseases is incompletely understood. Our long- term goal is to understand the mechanism of WNV pathogenesis. In this proposal, we will focus on the role of one specific ?? T cell subtype- namely V?4+ T cells in WNV-induced encephalitis. We have previously shown that ?? T cells, the non-classical T cell population, are important for early control of WNV dissemination. In further investigation of the role of ?? T cell subsets in WNV infection, we have found that antibody depletion of V?1+ T cells enhances host susceptibility;while depletion of V??? + T cells reduces host susceptibility. Splenic V?1+ T cells expand dramatically at the early stage of WNV infection and produce significant amounts of IFN-?, data which lead us to suggest a role in protective immunity. In contrast, V?4+ T cells expand modestly in response to infection. Moreover, our data show that the aged mice are more susceptible to WNV infection than are young mice. Aged mice exhibit a slower and reduced response by V?1+ T cells, while maintaining a higher number of V??4+ T cells at the early stage of infection. Based on these facts, we hypothesize that V??4+ T cells are involved in the regulation of WNV pathogenesis. In Specific Aim1, we will further investigate the pathogenic effect of V??4+ T cells during WNV infection. In Specific Aim 2, we will attempt to understand the mechanisms by which V??4+ T cells regulate host immunity during WNV infection. WNV has now induced the largest outbreaks of viral encephalitis in North America and has become a public health concern. Results from this study will help to enhance our understanding of viral pathogenesis;they will also lead to the development of new strategies to prevent and treat WNV-induced encephalitis. PUBLIC HEALTH RELEVANCE: West Nile virus (WNV), a vector-borne pathogen, has resulted in annual outbreaks of viral encephalitis in North America since 1999. Although immune responses to WNV have been the subject of intense investigation, little is known about the role of immune-mediated pathology, especially the role of T cells in WNV-related brain damage. In this proposal, we will focus on the study of one specific ?? T cell subtype, namely V??4+ T cells in WNV-induced encephalitis.